3D Genome Analysis reaches 10 bp resolution with Micro-C 3C

At Nexco Analytics we provide advanced bioinformatics services for 3D genome analysis, among several others we master as you can explore in our services page. Using state-of-the-art techniques such as Hi-C, Micro-C, ChIA-PET, HiChIP, and 3C, we help researchers reveal how genomes fold inside cells and how chromatin architecture drives gene regulation. And as we routinely bring to you in our blog for various other techniques, we stay at the forefront of 3D genome analysis by keeping our experts updated on the latest experiments, datasets, software, and publications.

Today we bring to you a new Nature study that demonstrates the power of enhanced Micro-C, which has achieved an unprecedented 10 base-pair resolution for mapping the Escherichia coli genome. This breakthrough uncovers previously invisible structures that govern the balance between gene activation and gene repression, with some superb insights and capabilities that might help you unlock your own next breakthrough.

Uncovering the 3D Genome: From Hi-C to Next-Generation Micro-C

Together with other techniques like 3C, traditional Hi-C analysis has provided valuable insights into genome folding — i.e. its structure in space, describing how genes, promoters, repressors and other bits of the genome that are far in sequence might actually be close in space. However, the resolution of Hi-C experiments is typically limited to 0.5–1 kb, leaving finer features of genome architecture hidden.

The new enhanced Micro-C chromosome conformation capture (Micro-C 3C or simply Micro-C) technique presented in the paper overcomes these limitations. By combining high-precision DNA digestion with optimized crosslinking, the Micro-C technique delivers single-nucleosome level resolution, that is as good as 10bp of resolution! In a way, this is like 50–100X magnification compared to traditional Hi-C, with which researchers can now see genome structures that Hi-C cannot resolve. And the paper reports some very interesting results of applying Micro-C 3C to the Escherichia coli genome.

Curious Structural Elements of the E. coli Genome

The study identified three fundamental classes of 3D genome structures in bacteria, known for short with the somewhat funny names of OPCIDs, CHINs, CHIDs:

• Operon-sized Chromosomal Interaction Domains (OPCIDs): These domains form when operons are actively transcribed. The DNA folds so that the promoter (start) and terminator (end) come into contact. The authors of the paper speculate that this enables RNA polymerase to recycle efficiently and sustain high transcription levels; essentially, it would fall off at the end of the gene right close to its beginning, allowing for a fast restart essential for genes undergoing high expression.
• Chromosomal Hairpins (CHINs): Compact hairpin-shaped DNA folds that appear in silent, non-transcribed regions.
• Chromosomal Hairpin Domains (CHIDs): Clusters of CHINs stabilized by specialized DNA-binding proteins. These structures repress horizontally transferred genes and maintain genome stability.

Notably, when some of the specific proteins that held CHINs and CHIDs together were deleted, or when cells were treated with netropsin (a small molecule that blocks binding of those proteins), CHINs and CHIDs collapsed and this collapse triggered a dramatic upregulation of silent genes and allowed new OPCIDs to emerge in their place. That is, by shutting down these proteins, CHINs and CHIDs were dissolved and structures compatible with expression were formed at high rates.

High-Resolution Micro-C Outperforms Conventional Hi-C Analysis

The ability to resolve structures at 10 base-pair resolution represents a step-change in genome biology. Compared with Hi-C, Micro-C offers higher resolution contact maps for detecting operon-level folding, improved detection of transcription-dependent domains (such as the OPCIDs), more precise mapping of protein–DNA interactions, and better integration with multi-omics datasets to enable a direct link between 3D genome folding and transcriptional output.

These advantages make Micro-C the preferred choice for projects seeking operon-scale regulatory insights, transcriptional dynamics, or drug-response studies.

Nexco’s Bioinformatics Services for 3D Genome Mapping

At Nexco we combine deep expertise in genome biology with powerful bioinformatics pipelines to help you extract insights from your data. Our services in this front include:

• Hi-C and and now Micro-C 3C Data Analysis, to go from raw sequencing data to high-resolution and now ultra-high resolution 3D contact maps.

• Multi-omics Integration, to correlate genome architecture with RNA-seq, ChIP-seq, ATAC-seq, or proteomics.

• Coming Up, 4D Transcriptomics
• Unveiling the 3D Organization of Tissues Through Spatial Multi-Omics

• Custom 3D Structural Modeling to identify transcription-driven domains and repressive structures such as CHINs and CHIDs; with sufficient detail we can also build near-atomistic models of the protein-nucleic acid complexes together with our experts in computational structural biology assisted by the most modern AI tools for molecular modeling. We can even help you visualize these 3D models in augmented or virtual reality!
• Comparative Genome Architecture, to analyze how stress, mutations, or drugs reshape genome folding; perhaps coupled to transcriptomics and other -omics to follow how these changes affect the cellular working.

Partner with Nexco for Hi-C, Micro-C, and 3D Genome Applications From Gene Regulation to Synthetic Biology and Beyond

With our expertise you can apply chromosome conformation capture analyses like those revisited here to virtually every subfield of biology. In microbiology, to uncover mechanisms of antibiotic resistance, stress response, and horizontal gene transfer. In synthetic biology, to design stable, efficient operons with optimized transcriptional recycling. In eukaryotic systems of course including humans, to study diseases of genetic origin, fundamental biology, etc. More broadly, to investigate if and how small molecules affect chromatin folding and transcriptional regulation. And the list keeps going!

At Nexco we will help you bring discoveries to your research. Whether you are planning Hi-C, Micro-C, ChIA-PET, HiChIP, or 3C experiments, or you already have data and need to process and analyze it, we are your trusted partner for 3D genome bioinformatics services.

Contact us today to learn how we can accelerate your research with cutting-edge chromosome conformation capture analysis and more 3D genome services.

References

Elementary 3D organization of active and silenced E. coli genome - Nature